The overall goal of this Exploratory/Developmental Research Grant is to discover the effects of endocannabinoids (eCB) in rostral ventrolateral medulla (RVLM) circuits that regulate cardiovascular function. The central nervous system is directly involved in regulation of arterial blood pressure, largely through actions of the sympathetic nervous system on renal function and abdominal vasculature. The RVLM is a critical component in the central pathways mediating cardiovascular regulation. Presympathetic RVLM neurons receive inputs from multiple areas of the brain and spinal cord, and mediate many cardiovascular reflexes. Hypertension may result from an imbalance between activity of sympathetic vasomotor neurons and those cells that inhibit them. This concept has been described as the "central neuron imbalance" hypothesis of hypertension. Little is known about normal RVLM neuronal regulation. The G protein-coupled cannabinoid type-1 receptor (CB1R) is expressed throughout the CNS, including the RVLM. Endogenous cannabinoids (eCB), (e. g. anandamide), act on both CB1R and transient receptor potential vanilloid type 1 (TRPV1), which are also expressed in the RVLM. The function of CB1R and TRPV1 receptors in RVLM is not known. This exploratory study will reveal the site and synaptic mechanisms of eCB actions in RVLM-mediated cardiovascular control, which have been elusive until now. A multi-disciplinary approach using immunohistochemistry, in vivo renal nerve and arterial blood pressure (ABP) recordings and in vitro patch-clamp recordings of synaptic currents in identified RVLM neurons to test the hypothesis that: 1) CB1R agonists will evoke sympathoexcitation when injected into the RVLM of anesthetized rats by decreasing GABAergic synaptic activity to presympathetic RVLM kidney-related neurons. 2) TRPV1 agonists will evoke sympathoinhibition when injected into the RVLM of anesthetized rats. Exploring these mechanisms will provide important insights about understanding the cellular mechanisms of cannabinoid actions on RVLM. This approach will also have clinical implications by providing direct evidence about the regulation of ABP by cannabinoids and therefore offer novel therapeutic strategies in the treatment of hypertension. PUBLIC HEALTH RELEVANCE: This study will reveal the site and effect of cannabinoids on a brainstem area involved in blood pressure control. Cannabinoid actions in the brainstem can have important clinical implications for the treatment of such medical conditions as hypertension.